Abstract
Acute myeloid leukaemia (AML) is a malignant disorder of the myeloid blood lineage characterized by impaired differentiation and increased proliferation of hematopoietic precursor cells. Recent technological advances have led to an improved understanding of AML biology but also uncovered the enormous cytogenetic and molecular heterogeneity of the disease. Despite this heterogeneity, AML is mostly managed by a ‘one‐size‐fits‐all’ approach consisting of intensive, highly toxic induction and consolidation chemotherapy. These treatment protocols have remained largely unchanged for the past several decades and only lead to a cure in approximately 30–35% of cases. The advent of targeted therapies in chronic myeloid leukaemia and other malignancies has sparked hope to improve patient outcome in AML. However, the implementation of targeted agents in AML therapy has been unexpectedly cumbersome and remains a difficult task due to a variety of disease‐ and patient‐specific factors. In this review, we describe current standard and investigational therapeutic strategies with a focus on targeted agents and highlight potential tools that might facilitate the development of targeted therapies for this fatal disease. The classes of agents described in this review include constitutively activated signalling pathway inhibitors, surface receptor targets, epigenetic modifiers, drugs targeting the interaction of the hematopoietic progenitor cell with the stroma and drugs that target the apoptotic machinery. The clinical context and outcome with these agents will be examined to gain insight about their optimal utilization.
Highlights
Personalized cancer therapy offers the hope to establish novel and more effective therapeutic standards for patients afflicted with this condition
Biomarker adapted treatment protocols have already been established in several cancers but many therapies are only temporarily effective[110,111,112]
Drug resistance to chemotherapy and targeted agents with subsequent relapse or progression remains a major problem in the treatment of cancer, including Acute Myeloid Leukemia (AML)[113]
Summary
Personalized cancer therapy offers the hope to establish novel and more effective therapeutic standards for patients afflicted with this condition. The IDHENTIFY phase III clinical trial is comparing enasidenib,to standard of care for older patients with relapsed/refractory IDH2 mutant AML Both AG-120 and enasidenib are being investigated in newly diagnosed AML with IDH1 and/or IDH2 mutations, in combination with intensive chemotherapy, as well as with azacitidine in unfit patients. Vorinostat was more recently studied in combination with induction chemotherapy in a phase 3 trial which was aborted due to lack of improvement over standard induction alone[77] It has been safely combined with azacitidine and has demonstrated efficacy in MLL-rearranged AML at relapse with response rates of 35% [78] in this high-risk subset of AML patients. Further refinement of these methods will be critical to their usefulness both clinically and in pre-clinical drug development
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